Natural gas is currently one of the most economical forms of carbon as it is both highly abundant and is the least expensive form of energy other than coal. Moreover, unlike sugar, natural gas is a highly reduced source of carbon, allowing conversion of the entire feedstock to highly reduced products. Methanotrophs have the innate ability to “upgrade” natural gas, by oxidizing methane as the sole carbon source to support cellular metabolism and growth. Unlike many industrial hosts, methanotrophs are challenging to genetically engineer as the requisite tools are generally not available and detailed microbial regulatory and physiological information are lacking. Intrexon’s synthetic biology team has developed an advanced suite of tools that enables rapid manipulation of methanotrophic organisms including gene knock in/out, direct transformation/electroporation, and plasmid-based expression systems. Using these tools, we have generated methanotroph strains that are capable of upgrading natural gas to fuels and chemicals.